9-Aminoacyl tetracycline compounds and methods of use thereof

ABSTRACT

A compound of formula (I):

RELATED APPLICATIONS

[0001] This application claims priority to U.S. patent application Ser.No. 10/295,708, entitled “9-Aminoacyl Tetracycline Compounds and Methodsof Use Thereof,” filed Nov. 15, 2002; U.S. patent application Ser. No.10/097,095, entitled “9-Aminoacyl Tetracycline Compounds and Methods ofUse Thereof,” filed Mar. 12, 2002; which claims priority to EuropeanPatent Application Serial No. 01500065.6, filed on Mar. 13, 2001,entitled “Medicamentos”. The entire contents of each aforementionedapplications are hereby incorporated herein by reference in theirentirety.

FIELD OF THE INVENTION

[0002] The present invention relates to a novel class of chemicalcompounds and to their use in medicine. In particular, the inventionconcerns novel tetracycline derivatives, methods for their preparation,pharmaceutical compositions containing them and their use as antibioticagents.

BACKGROUND OF THE INVENTION

[0003] Tetracycline derivatives are known for treating bacterialinfections. However, there remains a need for tetracycline derivativesfor the treatment of Gram-positive, Gram-negative and community acquiredinfections. Moreover, there remains a need for tetracycline derivativeseffective against tetracycline resistant strains.

DETAILED DESCRIPTION OF THE INVENTION

[0004] The present invention provides compounds of formula (I):

[0005] wherein:

[0006] R represents hydrogen, halogen, C₁₋₆alkyl or NRaRb;

[0007] R¹ represents hydrogen, C₁₋₆alkyl or together R¹ and R³ representa CH₂ moiety;

[0008] R² represents hydrogen, —OC₁₋₆alkyl, —O(O)C₁₋₆alkyl or hydroxy;

[0009] R³ represents hydrogen, hydroxy or together R³ and R¹ represent aCH₂ moiety;

[0010] R⁴ represents hydrogen or C₁₋₆alkyl;

[0011] R⁵ represents hydrogen, C₁₋₆alkyl, or C₁₋₆alkoxycarbonyl;

[0012] X represents NRxRy or —OC₁₋₆alkyl optionally substituted by oneor more groups selected from hydroxy, methoxy, halogen, amino andtrifluoromethyl; Ra and Rb independently represent hydrogen orC₁₋₆alkyl;

[0013] Rx and Ry independently represent hydrogen, benzyl,C₃₋₆cycloalkyl, C₃₋₆alkenyl, C₃₋₆alkynyl, C₁₋₆alkyl optionallysubstituted by one or more groups selected from hydroxy, methoxy,halogen, NRaRb and trifluoromethyl, —C₁₋₆alkylcycloalkyl,—C₁₋₆alkylheterocycle, C₁₋₆alkylamino and C₁₋₆alkylthio or together Rxand Ry form a heterocycle, and pharmaceutically acceptable derivativesand solvates thereof.

[0014] Compounds of formula (I) contain at least one asymmetric centre,denoted by *, and thus may exist as enantiomers or diastereoisomers. Itis to be understood that the invention includes each such isomer, eitherin substantially pure form or admixed in any proportion with one or moreother isomers of the compounds of formula (I). The preferredstereochemistry at the centre where R¹ and R³ are substituents is whenR¹ is H, R³ is in the alpha-configuration (downwards). The preferredstereochemistry at the centre where R² is a substituent is alpha(downwards). The preferred stereochemistry at the centre where N(Me)₂ isa substituent in the A ring is alpha (downwards).

[0015] The term “pharmaceutically acceptable derivative” as used hereinrefers to any pharmaceutically acceptable salt, or metabolically labilederivative of a compound of formula (I), for example a derivative of anamine group, which, upon administration to the recipient, is capable ofproviding (directly or indirectly) a compound of formula (I). It will beappreciated by those skilled in the art that the compounds of formula(I) may be modified to provide pharmaceutically acceptable derivativesthereof at any of the functional groups in the compounds of formula (I).Such derivatives are clear to those skilled in the art, without undueexperimentation, and with reference to the teaching of Burger'sMedicinal Chemistry And Drug Discovery, 5th Edition, Vol 1: PrinciplesAnd Practice, which is incorporated herein by reference. For examplecompounds of formula (I) may be N-alkylated in the presence offormaldehyde and an amine such as methylamine to give the correspondingMannich base adducts.

[0016] Salts and solvates of compounds of formula (I) which are suitablefor use in medicine are those wherein the counterion or associatedsolvent is pharmaceutically acceptable. However, salts and solvateshaving non-pharmaceutically acceptable counterions or associatedsolvents are within the scope of the present invention, for example, foruse as intermediates in the preparation of other compounds of formula(I) and their pharmaceutically acceptable derivatives, and solvates.

[0017] Suitable salts according to the invention include those formedwith both organic and inorganic acids or bases. Pharmaceuticallyacceptable acid addition salts include those formed fromtrifluoroacetic, hydrochloric, hydrobromic, hydroiodoic, sulphuric,citric, tartaric, phosphoric, lactic, pyruvic, acetic, succinic, oxalic,fumaric, maleic, oxaloacetic, methanesulphonic, ethanesulphonic,p-toluenesulphonic, benzenesulphonic, and isethionic acids.Pharmaceutically acceptable base salts include ammonium salts, alkalimetal salts such as those of sodium and potassium, alkaline earth metalsalts such as those of calcium and magnesium and salts with organicbases such as dicyclohexyl amine and N-methyl-D-glucamine.

[0018] Suitable solvates according to the invention include hydrates.

[0019] The term “alkyl”, as used herein to define a group or a part of agroup, unless otherwise stated, refers to a saturated straight orbranched alkyl chain containing from 1 to 6 carbon atoms. Examples ofsuch groups include without limitation methyl, ethyl, n-propyl,isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, neopentyl andhexyl.

[0020] The term “alkenyl”, as used herein to define a group or a part ofa group, unless otherwise stated, refers to a straight or branchedalkenyl chain containing from 2 to 6 carbon. Examples of such groupsinclude without limitation 1-ethenyl, 1-propenyl, allyl(2-propenyl),1-butenyl, 2-butenyl, 2-pentenyl.

[0021] The term “alkynyl”, as used herein to define a group or a part ofa group, unless otherwise stated, refers to a straight or branchedalkynyl chain containing from 3 to 6 carbon. Examples of such groupsinclude without limitation propynyl, butynyl or pentynyl.

[0022] The term “cycloalkyl” as used herein to define a group or a partof a group, unless otherwise stated, refers to a saturated alkyl ringcontaining from 3 to 6 carbon atoms. Examples of such groups includecyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0023] The term “alkylamino” as used herein to define a group or a partof a group, unless otherwise stated, refers to a saturated straight orbranched alkyl chain containing from 1 to 6 carbon atoms substituted byone or more amino groups. Examples of such groups include withoutlimitation methylamino and tert-butylamino.

[0024] The term “alkylthio” as used herein to define a group or a partof a group, unless otherwise stated, refers to a saturated straight orbranched alkyl chain containing from 1 to 6 carbon atoms substituted byone or more thiol groups. Examples of such groups include withoutlimitation methylthio and tert-butylthio.

[0025] The term “halogen” refers to a fluorine, chlorine, bromine oriodine atom. Suitably the halogen atom is selected from chlorine,bromine or iodine, preferably chlorine or bromine. Chlorine is mostpreferred.

[0026] The term “heterocycle”, as used herein refers to a 3, 4, 5 or 6membered saturated or unsaturated heterocyclic ring containing at leastone heteroatom selected from nitrogen, oxygen or sulphur. Suitableexamples include without limitation tetrahydrofuran, furan, thiophene,pyridine, pyrrole, 2-pyrroline, 3-pyrroline, pyrrolidine, imidazole,2-imidazoline, imidazolidine, pyrazole, 2-pyrazoline, pyrazoline,pyrazolidine, aziridine, 1,2,3-triazole, 1,2,4-triazole,1,2,3-thiadiazole, piperidine, morpholine, thiomorpholine andpiperazine. It will be appreciated by those skilled in the art that whenX represents NRxRy and together Rx and Ry form a heterocycle, theheterocylce will contain at least one nitrogen atom. Examples ofsuitable nitrogen containing herterocylces include, without limitation,pyrrole, 2-pyrroline, 3-pyrroline, pyrrolidine, imidazole,2-imidazoline, imidazolidine, pyrazole, 2-pyrazoline, pyrazoline,pyrazolidine, aziridine, 1,2,3-triazole, 1,2,4-triazole,1,2,3-thiadiazole, piperidine, morpholine, thiomorpholine andpiperazine.

[0027] Suitably, R is selected from hydrogen, methyl, chlorine andNRaRb. More suitably, R is selected from methyl, chlorine and NRaRb.Conveniently, R is selected from hydrogen, methyl, and NRaRb. Moreconveniently, R is selected from methyl, and NRaRb. Preferably, R isselected from hydrogen and NRaRb. More preferably, R is hydrogen.

[0028] Suitably, R¹ represents hydrogen, methyl or together R¹ and R³represent a CH₂ moiety. Conveniently, R¹ is selected from hydrogen andmethyl. More conveniently, R¹ is hydrogen. Preferably R¹ is methyl.

[0029] Suitably, R² is selected from hydrogen, methoxy and hydroxy. Moresuitably, R² is selected from hydrogen and hydroxy. Conveniently, R² ishydroxy. Preferably, R² is hydrogen.

[0030] Suitably, R³ represents hydrogen or hydroxy. Conveniently R³ ishydroxy. Preferably R³ is hydrogen.

[0031] Suitably, R⁴ represents methyl or hydrogen. Conveniently R⁴ ismethyl. Preferably, R⁴ is hydrogen.

[0032] Suitably, R⁵ represents methyl or hydrogen. Conveniently R⁵ ismethyl. Preferably, R⁵ is hydrogen.

[0033] Suitably, X represents NRxRy. Conveniently, X represents—OC₁₋₆alkyl.

[0034] Suitably, Ra and Rb independently represent hydrogen or methyl.Conveniently Ra and Rb are methyl. Preferably, Ra and Rb are hydrogen.

[0035] Suitably, Rx and Ry independently represent hydrogen, benzyl,C₃₋₆cycloalkyl, C₃₋₆alkenyl, C₁₋₆alkyl optionally substituted by one ormore groups selected from hydroxy, methoxy, and NRaRb,—C₁₋₃alkylcycloalkyl, —C₁₋₃alkylheterocycle, C₁₋₆alkylamino andC₁₋₆alkylthio or together Rx and Ry form a heterocycle. More suitably,Rx and Ry independently represent hydrogen, benzyl, C₃₋₆cycloalkyl,C₃₋₆alkenyl, C₁₋₆alkyl, —C₁₋₃alkylcycloalkyl, —C₁₋₃alkylheterocycle, ortogether Rx and Ry form a heterocycle. Conveniently, Rx and Ryindependently represent hydrogen, benzyl, C₃₋₆cycloalkyl, C₃₋₆alkenyl,C₁₋₆alkyl, or together Rx and Ry form a heterocycle. More conveniently,Rx and Ry independently represent hydrogen, benzyl, C₃₋₆cycloalkyl,C₃₋₆alkenyl and C₁₋₆alkyl. Preferably, Rx and Ry together form aheterocylcle.

[0036] When X represents —OC₁₋₆alkyl, X is suitably selected fromiso-propoxy and ethoxy.

[0037] Suitably, NRxRy is selected from MeNH, Me₂N, EtNH, Et₂N,CH₂CHCH₂NH, CH₃OCH₂CH₂NH, CH₃(CH₃)₂CHCH₂CH₂NH, n-PrNH, n-Pr₂N, i-PrNH,i-Pr₂N, t-BuNH, t-Bu₂N, n-HexNH, n-Hex₂N, (CH₃)₂NCH₂CH₂NH,cyclopropyl-NH, aziridine, cyclobutyl-NH, cyclopentyl-NH, pyrrolidine,cyclohexylNH, propenyl-NH, benzyl-NH, piperidine, piperazine, morpholineand thiomorpholine. Preferably, NRxRy is selected from MeNH, Me₂N, EtNH,CH₂CHCH₂NH, CH₃OCH₂CH₂NH, n-PrNH, i-PrNH, n-HexNH, (CH₃)₂NCH₂CH₂NH,CH₃(CH₃)₂CHCH₂CH₂NH, cyclopropyl-NH, aziridine, cyclobutyl-NH,cyclopentyl-NH, pyrrolidine, cyclohexylNH, propenyl-NH, benzyl-NH,piperidine, piperazine and thiomorpholine.

[0038] Suitably the compound of formula (I) is derivatised from anatural tetracycline like compound. Examples of natural tetracyclinelike compounds include tetracycline, chlortetracycline, oxytetracycline,demeclocycline, methacycline, sancycline, doxycycline, and minocycline.Preferably the natural tetracycline like compound is selected fromsancycline, doxycycline, and minocycline, most preferably doxycyclineand sancycline.

[0039] It is to be understood that the present invention covers allcombinations of suitable, convenient and preferred groups describedhereinabove.

[0040] In one embodiment, R is hydrogen, R¹ is methyl, R² is hydroxy, R³is hydrogen, R⁴ is hydrogen, R⁵ is hydrogen, X represents NRxRy and Rxand Ry are independently selected from hydrogen, benzyl, C₃₋₆cycloalkyl,C₃₋₆alkenyl, C₁₋₆alkyl optionally substituted by one or more groupsselected from hydroxy, methoxy, and NRaRb, —C₁₋₃alkylcycloalkyl,—C₁₋₃alkylheterocycle, C₁₋₆alkylamino and C₁₋₆alkylthio or together Rxand Ry form a heterocycle.

[0041] In one embodiment, R is hydrogen, R¹ is hydrogen, R² is hydrogen,R³ is hydrogen, R⁴ is hydrogen, R⁵ is hydrogen, X represents NRxRy and Xrepresents NRxRy and Rx and Ry are independently selected from hydrogen,benzyl, C₃₋₆cycloalkyl, C₃₋₆alkenyl, C₁₋₆alkyl optionally substituted byone or more groups selected from hydroxy, methoxy, and NRaRb,—C₁₋₃alkylcycloalkyl, —C₁₋₃alkylheterocycle, C₁₋₆alkylamino andC₁₋₆alkylthio or together Rx and Ry form a heterocycle.

[0042] In one embodiment, R is hydrogen, R¹ is methyl, R² is hydroxy, R³is hydrogen, R⁴ is hydrogen, R⁵ is hydrogen, X represents NRxRy andNRxRy is selected from MeNH, Me₂N, EtNH, CH₂CHCH₂NH, CH₃OCH₂CH₂NH,n-PrNH, i-PrNH, n-HexNH, (CH₃)₂NCH₂CH₂NH, CH₃(CH₃)₂CHCH₂CH₂NH,cyclopropyl-NH, aziridine, cyclobutyl-NH, cyclopentyl-NH, pyrrolidine,cyclohexylNH, propenyl-NH, benzyl-NH, piperidine, piperazine andthiomorpholine.

[0043] In one embodiment, R is hydrogen, R¹ is hydrogen, R² is hydrogen,R³ is hydrogen, R⁴ is hydrogen, R⁵ is hydrogen, X represents NRxRy andNRxRy is selected from MeNH, Me₂N, EtNH, CH₂CHCH₂NH, CH₃OCH₂CH₂NH,n-PrNH, i-PrNH, n-HexNH, (CH₃)₂NCH₂CH₂NH, CH₃(CH₃)₂CHCH₂CH₂NH,cyclopropyl-NH, aziridine, cyclobutyl-NH, cyclopentyl-NH, pyrrolidine,cyclohexylNH, propenyl-NH, benzyl-NH, piperidine, piperazine andthiomorpholine.

[0044] In one embodiment, R is hydrogen, R¹ is methyl, R² is hydroxy, R³is hydrogen, R⁴ is hydrogen, R⁵ is hydrogen and X represents —OC₁₋₆alkyloptionally substituted by one or more groups selected from hydroxy,methoxy, halogen, amino and trifluoromethyl.

[0045] In one embodiment, R is hydrogen, R¹ is hydrogen, R² is hydrogen,R³ is hydrogen, R⁴ is hydrogen, R⁵ is hydrogen and X represents—OC₁₋₆alkyl optionally substituted by one or more groups selected fromhydroxy, methoxy, halogen, amino and trifluoromethyl.

EXAMPLES OF COMPOUNDS OF FORMULA (I) INCLUDE

[0046][4S-(4a,5a,12a)]-4,7-Bis(dimethylamino)-9-[(ethoxycarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphtacenecarboxamide;

[0047][4S-(4a,5,5a,6,12a)]-4-(Dimethylamino)-9-[1-(ethoxycarbonyl)ethyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphtacenecarboxamide;

[0048][4S-(4a,5,5a,6,12a)]-4-(Dimethylamino)-9-[(ethoxycarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphtacenecarboxamide;

[0049][4S-(4a,5,5a,6,12a)]-4-(Dimethylamino)-9-[(N,N-dimethylaminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphtacenecarboxamide;

[0050][4S-(4a,5,5a,6,12a)]-4-(Dimethylamino)-9-[(N-isopropylaminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphtacenecarboxamide;

[0051][4S-(4a,5,5a,6,12a)]-4-(Dimethylamino)-9-[(N-(2-propenyl)aminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphtacenecarboxamide;

[0052][4S-(4a,5,5a,6,12a)]-4-(Dimethylamino)-9-[(1-pyrrolidinocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphtacenecarboxamide;

[0053][4S-(4a,5,5a,6,12a)]-4-(Dimethylamino)-9-[(iso-propoxycarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphtacenecarboxamide;

[0054][4S-(4a,5,5a,6,12a)]-4-(Dimethylamino)-9-[(N-benzylaminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphtacenecarboxamide;

[0055][4S-(4a,5,5a,6,12a)]-4-(Dimethylamino)-9-[(N-ethylaminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphtacenecarboxamide;

[0056][4S-(4a,5,5a,6,12a)]-4-(Dimethylamino)-9-[(N-cyclohexylaminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphtacenecarboxamide;

[0057][4S-(4a,5,5a,6,12a)]-4-(Dimethylamino)-9-[(1-piperidinocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphtacenecarboxamide;

[0058][4S-(4a,5,5a,6,12a)]-4-(Dimethylamino)-9-[(N-(2-methoxyethyl)amino-carbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphtacenecarboxamide;

[0059][4S-(4a,5,5a,6,12a)]-4-(Dimethylamino)-9-[(N-cyclobutylaminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphtacenecarboxamide;

[0060][4S-(4a,5,5a,6,12a)]-4-(Dimethylamino)-9-[(N-(2-tetrahydrofurylmethyl)-aminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphtacenecarboxamide;

[0061][4S-(4a,5,5a,6,12a)]-4-(Dimethylamino)-9-[(N-(3,3-dimethylbutyl)aminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphtacenecarboxamide;

[0062][4S-(4a,5,5a,6,12a)]-4-(Dimethylamino)-9-[(N-methylaminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphtacenecarboxamide;

[0063][4S-(4a,5,5a,6,12a)]-4-(Dimethylamino)-9-[(N-cyclopropylaminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphtacenecarboxamide;

[0064][4S-(4a,5a,12a)]-4,7-Bis(dimethylamino)-9-[(N,N-dimethylaminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphtacenecarboxamide;

[0065][4S-(4a,5a,12a)]-4-(Dimethylamino)-9-[(N,N-dimethylaminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphtacenecarboxamide;

[0066][4S-(4a,5a,12a)]-4-(Dimethylamino)-9-[(N-isopropylaminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphtacenecarboxamide;

[0067][4S-(4a,5a,12a)]-4-(Dimethylamino)-9-[(N-ethylaminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphtacenecarboxamide;

[0068][4S-(4a,5a,12a)]-4-(Dimethylamino)-9-[(N-(2-N′,N′-dimethylaminoethyl)aminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphtacenecarboxamide;

[0069][4S-(4a,5a,12a)]-4-(Dimethylamino)-9-[(N-cyclopropylaminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphtacenecarboxamide;

[0070][4S-(4a,5a,12a)]-4-(Dimethylamino)-9-[(1-pyrrolidinoaminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphtacenecarboxamide;

[0071][4S-(4a,5a,12a)]-4-(Dimethylamino)-9-[(N-cyclopentylaminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphtacenecarboxamide;

[0072][4S-(4a,5a,12a)]-4-(Dimethylamino)-9-[(N-(2-propenyl)aminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphtacenecarboxamide;

[0073][4S-(4a,5a,12a)]-4-(Dimethylamino)-9-[(N-methylaminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphtacenecarboxamide;

[0074][4S-(4a,5a,12a)]-4-(Dimethylamino)-9-[(N-benzylaminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphtacenecarboxamide;

[0075][4S-(4a,5a,12a)]-4-(Dimethylamino)-9-[(N-cyclobutylaminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphtacenecarboxamide;

[0076] 4S-(4aα, 5α, 5aα, 6α,12aα)-4,7-(bis-dimethylamino)-9-[1-(ethoxycarbonyl)ethyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide;

[0077] [4S-(4aα, 5α, 5aα, 6α,12aα)-4-(dimethylamino)-9-[(ethoxycarbonyl)-2-methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-1,11-dioxo-6-methyl-2-naphthacenecarboxamide;

[0078] [4S-(4aα, 5α, 5aα, 6α,12aα)-4-(dimethylamino)-9-[(ethoxycarbonyl)-2-carbonylethoxymethyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-1,11-dioxo-6-methyl-2-naphthacenecarboxamide.

[0079] References herein after to compounds of the invention includecompounds of formula (I) and their pharmaceutically acceptablederivatives and solvates.

[0080] As demonstrated in the assays described below the compounds ofthe present invention show activity against the most importantpathogens, including gram positive bacteria such as S. pneumoniae and S.aureus, and gram negative organisms such as H. influenzae, M.catarrhalis and E. coli. In addition, these compounds are active againstgram positive and gram negative tetracycline resistant bacterialstrains, including those with resistance mediated by efflux pumps andribosome protection.

[0081] Accordingly, in a further aspect the present invention provides amethod for the treatment of a tetracycline compound responsive state ina subject, preferably a human, which comprises administering to thesubject an effective amount of a compound of formula (I) orpharmaceutically acceptable derivative or solvate thereof.

[0082] In the alternative, there is provided a compound of formula (I)or a pharmaceutically acceptable derivative or solvate thereof, for usein medical therapy, particularly, for use in the manufacture of a medicament for the treatment of a tetracycline compound responsive state.

[0083] The term “tetracycline compound responsive state” includes astate which can be treated, prevented, or otherwise ameliorated by theadministration of a compound of formula (I) or pharmaceuticallyacceptable derivative or solvate thereof. Tetracycline compoundresponsive states include bacterial infections (including those whichare resistant to other tetracycline compounds), cancer, diabetes, andother states for which tetracycline compounds have been found to beactive (see, for example, U.S. Pat. Nos. 5,789,395; 5,834,450; and5,532,227). Compounds of the invention can be used to prevent or controlimportant human and veterinary diseases such as respiratory tractinfections, systemic infections and some local infections. Moreparticularly, compounds of the invention can be used to prevent orcontrol diarrhoea, urinary tract infections, infections of skin and skinstructure, ear, nose and throat infections, wound infection, mastitisand the like. In addition, methods for treating neoplasms usingtetracycline compounds of the invention are also included (van derBozert et al., Cancer Res., 48:6686-6690 (1988)). In one embodiment, thetetracycline compound is used to treat a bacterial infection. In afurther embodiment, the tetracycline compound is used to treat abacterial infection that is resistant to other tetracycline antibioticcompounds.

[0084] For the avoidance of doubt, the term ‘treatment’ as used hereinincludes prophylactic therapy.

[0085] Bacterial infections may be caused by a wide variety of grampositive and gram negative bacteria. The compounds of formula (I) areuseful as antibiotics against organisms which are resistant to othertetracycline compounds. The antibiotic activity of the compounds offormula (I) may be determined using the method discussed in theBiological Example below, or by using the in vitro standard brothdilution method described in Waitz, J. A., National Committee forClinical Laboratory Standards, Approved Standard M7-T2, vol. 10, no. 8,pp. 13-20, 2^(nd) edition, Villanova, Pa. (1990).

[0086] The compounds of the invention may also be used to treatinfections traditionally treated with tetracycline compounds such as,for example, rickettsiae; a number of gram-positive and gram-negativebacteria; and the agents responsible for lymphogranuloma venereum,inclusion conjunctivitis and psittacosis. The compounds of formula (I)may be used to treat infections of pneumococci, Salmonella, E. coli, S.aureus or E. faecalis.

[0087] The term “effective amount” of the compound of formula (I) isthat amount necessary or sufficient to treat or prevent a tetracyclinecompound responsive state. The effective amount can vary depending onsuch factors as the size and weight of the subject, the type of illness,or the particular tetracycline compound. One of ordinary skill in theart would be able to study the aforementioned factors and make thedetermination regarding the effective amount of the compound of formula(I) or a pharmaceutically acceptable derivative or solvate thereofwithout undue experimentation.

[0088] The invention also pertains to methods of treatment againstmicro-organism infections and associated diseases. The methods includeadministration of an effective amount of one or more compounds offormula (I) or a pharmaceutically acceptable derivative or solvatethereof to a subject. Preferably the subject is a mammal e.g., a human.

[0089] For human use, a compound of the formula (I) can be administeredas raw drug substance, but will generally be administered in admixturewith a pharmaceutically acceptable carrier selected with regard to theintended route of administration and standard pharmaceutical practice.

[0090] Accordingly, the present invention further provides apharmaceutical formulation comprising a compound of formula (I) or apharmaceutically acceptable derivative or solvate thereof, and one ormore pharmaceutically acceptable carriers.

[0091] The term pharmaceutically acceptable carrier includes substancescapable of being coadministered with the compounds of formula (I), andwhich allow performance of the intended function, e.g., treat or preventa tetracycline compound responsive state. Suitable pharmaceuticallyacceptable carriers include but are not limited to water, saltsolutions, alcohol, vegetable oils, polyethylene glycols, gelatin,lactose, amylose, magnesium stearate, talc, silicic acid, viscousparaffin, perfume oil, fatty acid monoglycerides and diglycerides,petroethral fatty acid esters, hydroxymethyl-cellulose,polyvinylpyrrolidone, etc.

[0092] The pharmaceutical preparations can be sterilised and if desiredmixed with auxiliary agents, e.g., lubricants, preservatives,stabilisers, wetting agents, emulsifiers, salts for influencing osmoticpressure, buffers, colourings, flavourings and/or aromatic substancesand the like which do not deleteriously react with the compounds of theinvention.

[0093] The compounds of the invention may be administered alone or incombination with pharmaceutically acceptable carriers or diluents. Thecompounds of the invention may be administered via oral, parenteral ortopical routes. The administration may be carried out in single ormultiple doses. The compounds of the invention may be administered in awide variety of different dosage forms, for example they may be combinedwith various pharmaceutically acceptable inert carriers in the form oftablets, capsules, lozenges, troches, hard candies, powders, sprays,creams, salves, suppositories, jellies, gels, pastes, lotions,ointments, aqueous suspensions, injectable solutions, elixirs, syrups,and the like. Such carriers include solid diluents or fillers, sterileaqueous media and various non-toxic organic solvents, etc. Moreover,oral pharmaceutical compositions may be sweetened and/or flavoured. Ingeneral, the compounds of the invention are present in such dosage formsat concentration levels ranging from about 5.0% to about 70% by weight.

[0094] For oral administration, tablets may contain various excipientssuch as microcrystalline cellulose, sodium citrate, calcium carbonate,dicalcium phosphate and glycine may be employed along with variousdisintegrants such as starch (and preferably corn, potato or tapiocastarch), alginic acid and certain complex silicates, together withgranulation binders like polyvinylpyrrolidone, sucrose, gelatin andacacia. Additionally, lubricating agents such as magnesium stearate,sodium lauryl sulphate and talc may be employed. Solid compositions of asimilar type may also be employed as fillers in gelatin capsules;preferred materials in this connection also include lactose or milksugar as well as high molecular weight polyethylene glycols. Whenaqueous suspensions and/or elixirs are desired for oral administration,the active ingredient may be combined with various sweetening orflavouring agents, colouring matter or dyes, and, if so desired,emulsifying and/or suspending agents, together with diluents such aswater, ethanol, propylene glycol, glycerin and various combinationsthereof.

[0095] For parenteral administration (including intraperitoneal,subcutaneous, intravenous, intradermal or intramuscular injection),solutions of compounds of the invention in either sesame or peanut oilor in aqueous propylene glycol may be employed. The aqueous solutionsmay be buffered (preferably pH greater than 8) if necessary and theliquid diluent first rendered isotonic. These aqueous solutions aresuitable for intravenous injection purposes. The oily solutions aresuitable for intraarticular, intramuscular and subcutaneous injectionpurposes. The preparation of all these solutions under sterileconditions is readily accomplished by standard pharmaceutical techniqueswell known to those skilled in the art. For parenteral administration,examples of suitable preparations include solutions, preferably oily oraqueous solutions as well as suspensions, emulsions, or implants,including suppositories. Compounds of the invention may be formulated insterile form in multiple or single dose formats. For example thecompounds of the invention may be dispersed in a fluid carrier such assterile saline or 5% saline dextrose solutions commonly used withinjectables.

[0096] The compounds of the invention may be administered topically forexample when treating inflammatory conditions of the skin. Examples ofmethods of topical administration include transdermal, buccal orsublingual application. For topical applications, therapeutic compoundscan be suitably admixed in a pharmacologically inert topical carriersuch as a gel, an ointment, a lotion or a cream. Such topical carriersinclude water, glycerol, alcohol, propylene glycol, fatty alcohols,triglycerides, fatty acid esters, or mineral oils. Other possibletopical carriers are liquid petrolatum, isopropylpalmitate, polyethyleneglycol, ethanol 95%, polyoxyethylene monolauriate 5% in water, sodiumlauryl sulphate 5% in water, and the like. In addition, materials suchas anti-oxidants, humectants, viscosity stabilisers and the like alsomay be added if desired.

[0097] For enteral application, particularly suitable are tablets,dragees or capsules having talc and/or carbohydrate carrier binder orthe like, the carrier preferably being lactose and/or corn starch and/orpotato starch. A syrup, elixir or the like can be used wherein asweetened vehicle is employed. Sustained release compositions can beformulated including those wherein the active component is protectedwith differentially degradable coatings, e.g., by microencapsulation,multiple coatings, etc.

[0098] In addition to treatment of human subjects, the therapeuticmethods of the invention also will have significant veterinaryapplications, e.g. for treatment of livestock such as cattle, sheep,goats, cows, swine and the like; poultry such as chickens, ducks, geese,turkeys and the like; horses; and pets such as dogs and cats.

[0099] It will be appreciated that the actual amount of the compound ofthe invention used in a given therapy will vary according to thespecific compound being utilised, the particular compositionsformulated, the mode of application, the particular site ofadministration, etc. Optimal administration rates for a given protocolof administration can be readily ascertained by those skilled in the artwithout undue burden.

[0100] In general, compounds of the invention for treatment can beadministered to a subject in dosages used in prior tetracyclinetherapies. See, for example, the Physicians' Desk Reference. Forexample, a suitable effective dose of one or more compounds of theinvention will be in the range of from 0.01 to 100 milligrams perkilogram of body weight of recipient per day, preferably in the range offrom 0.1 to 50 milligrams per kilogram body weight of recipient per day,more preferably in the range of 1 to 20 milligrams per kilogram bodyweight of recipient per day. The desired dose is suitably administeredonce daily, or several sub-doses, e.g. 2 to 5 sub-doses, areadministered at appropriate intervals through the day, or otherappropriate schedule.

[0101] It will also be understood that normal, conventionally knownprecautions will be taken regarding the administration of tetracyclinesgenerally to ensure their efficacy under normal use circumstances.Especially when employed for therapeutic treatment of humans and animalsin vivo, the practitioner should take all sensible precautions to avoidconventionally known contradictions and toxic effects. Thus, theconventionally recognised adverse reactions of gastrointestinal distressand inflammations, the renal toxicity, hypersensitivity reactions,changes in blood, and impairment of absorption through aluminium,calcium, and magnesium ions should be duly considered in theconventional manner.

[0102] The compounds and pharmaceutical compositions of the inventionmay be administered alone or in combination with other known compoundsand compositions for treating tetracycline compound responsive states ina mammal e.g. a human. The term in combination with a known compound orcomposition is intended to include simultaneous, concomitant andsequential administration.

[0103] Accordingly, the present invention provides a combinationcomprising a compound of formula (I) or a pharmaceutically acceptablederivative or solvate thereof, and a further active ingredient suitablefor treating tetracycline compound responsive states in a mammal e.g. ahuman.

[0104] Compounds of Formula (I) and pharmaceutically acceptablederivatives and solvates thereof may be prepared by general methodsoutlined hereinafter where the groups R, R¹, R², R³, R⁴, R⁵, X, Ra, Rb,Rx and Ry have the meaning defined for compounds of formula (I) unlessotherwise stated.

[0105] According to a further aspect of the invention, there is provideda process (A) for preparing a compound of Formula (I) wherein R⁵ ishydrogen and X is NRxRy or a pharmaceutically acceptable derivative orsolvate thereof which process comprises reacting a compound of formula(II) with a compound of formula (III) under dehydrating conditions forexample in the presence of acetic acid, methanol and water and thensubjecting the product to a reducing agent such as sodiumcyanoborohydride.

[0106] According to a further aspect of the invention, there is provideda process (B) for preparing a compound of Formula (I) wherein R⁵ ishydrogen and X is —OC₁₋₆ alkyl or a pharmaceutically acceptablederivative or solvate thereof which process comprises reacting acompound of formula (II) with a compound of formula (IV) underdehydrating conditions for example in the presence of acetic acid,methanol and water, subjecting the adduct to a reducing agent such assodium cyanoborohydride and then reacting the N-glycyl derivative withthe appropriate alcohol (HOC₁₋₆alkyl) in the presence of a catalyst suchas thionyl chloride.

[0107] According to a further aspect of the invention, there is provideda process (C) for the preparation of a compound of Formula (I) whereinR⁵ is C₁₋₆alkyl or C₁₋₆alkoxycarbonyl and X is an C₁₋₆alkoxy group, analkylamino group (e.g., NR^(x)R^(y)) or a carboxylic acid derivative, ora pharmaceutically acceptable derivative or solvate thereof. The processcomprises reacting a compound of Formula (II) with a compound of formula(V) under conditions such that the compound is formed.

[0108] Compounds of formula (III) may be prepared by reacting compoundsof formula (VI) with sodium periodate in wet dichloromethane.

[0109] Alternatively, compounds of formula (III) may be prepared byreacting compounds of formula (VII) with an appropriate amine of formulaHNRxRy and then reacting the adduct with sodium periodate in wetdichloromethane.

SYNTHETIC EXAMPLES

[0110] 9-amino tetracycline derivatives were prepared according to thefollowing general procedures:

[0111] R, R¹, R³, R²═H (sancycline) (a) NBS/conc. H₂SO₄, 0° C.; (b) 10%HNO₃/conc. H₂SO₄; (c) H₂, Pd/C, MeOH, HCl. Ref: J. Boothe, J. J. Hlavka,J. P. Petisi, J. L. Spencer, J. Am. Chem. Soc., 1960, 82, 1253-4.

[0112] R=NMe₂, R¹, R³, R²=H (minocycline) (a) HNO₃/conc. H₂SO₄; (b) H₂,Pd/C, MeOH/HCl. Ref: P. Sum, V. L. Lee, R. T. Testa, J. J. Hlavka, G. A.Ellestad, J. D. Bloom, Y. Gluzman, F. P. Tally, J. Med. Chem, 1994, 37,184-8.

[0113] R=H, R¹=H, R³(alpha)=Me, R²(alpha)=OH (doxycycline) (a)NaNO₃/conc. H₂SO₄; (b) H₂, Pd/C, MeOH. Ref: T. C. Barden, B. L.Buckwalter, R. T. Testa, P. J. Petersen, V. L. Lee, J. Med. Chem. 1994,37, 3205-11.

[0114] General Procedure (A)

[0115] A solution of the 9-amino derivative (0.17 mmol) in a mixture ofmethanol (14 ml), acetic acid (0.7 ml) and water (0.7 ml) is treatedwith the corresponding aldehyde (0.20 mmol). After stirring at roomtemperature for 5 min, solid sodium cyanoborohydride (0.20 mmol) isadded and the reaction solution is stirred for 1 hour. A suspension ofthe reaction product is then obtained either by dropwise addition ofcool ether into the reaction solution (in the case of minocyclinederivatives) or to the dry material after evaporating the solvent (inthe case of sancy and doxycycline derivatives). Filtration of thissuspension through a glass-sintered funnel affords a crude materialwhich is purified by semi-preparative hplc (water/acetonitrilegradient). Water (0.1% trifluoroacetic acid)/acetonitrile (0.1%trifluoroacetic acid), gradient 15 to 50% acetonitrile for 45 min; Lunacolumn (10 microns, C-8, 250×21,20 mm); compounds were detected by usingUV light of a 280 nm wavelength.

[0116] General Procedure (B)

[0117] A solution of the 9-amino derivative (0.17 mmol) in a mixture ofmethanol (14 ml), acetic acid (0.7 ml) and water (0.7 ml) is treatedwith the corresponding aldehyde (0.20 mmol) to afford the 9-(N-glycyl)which is treated with thionyl chloride (10 ul) and the appropriatealcohol. The solution is stirred at room temperature for 20 h.Evaporation of the resulting reaction solution gives rise to a residuewhich is treated with ether. The resulting suspension is filteredthrough a glass-sintered funnel to afford a crude material which ispurified by semi-preparative hplc (water/acetonitrile gradient). Water(0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid),gradient 15 to 50% acetonitrile for 45 min; Luna column (10 microns,C-8, 250×21,20 mm); compounds were detected by using UV light of a 280nm wavelength.

[0118] General Procedure (C)

[0119] A 9-amino derivative (0.10 mmol) is dissolved inN-methylpyrrolidinone (1.0 mL) and treated with excess (0.40 mmol) ofthe corresponding bromocarbonyl compound. After stirring for 4 hours at60-65° C., the reaction mixture is cooled and is dripped slowly intocold ether producing the crude product. The solid can then be collectedby filtration, and purified by preparative chromatography (phosphatebuffer 0.1 M+0.001 M Na₂EDTA and methanol gradient, 30% to 100% over 30minutes), C18 solid-phase, UV detection at 280 nm). The productfractions can then be isolated, extracted into butanol (3×10 ml), driedover Na₂SO₄, and the solvent can be removed in vacuo to yield theproduct.

[0120] The following compounds were prepared according to the abovedescribed general methods:

Example 1

[0121][4S-(4a,5a,12a)]-4,7-Bis(dimethylamino)-9-[(ethoxycarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphtacenecarboxamide

[0122] MS (e.s.+): m/z 559.30 (M⁺+H)

Example 2

[0123][4S-(4a,5,5a,6,12a)]-4-(Dimethylamino)-9-[1-(ethoxycarbonyl)ethyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphtacenecarboxamide

[0124] MS (e.s.+): m/z 560.2 (M⁺+H)

Example 3

[0125][4S-(4a,5,5a,6,12a)]-4-(Dimethylamino)-9-[(ethoxycarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphtacenecarboxamide

[0126] MS (e.s.+): m/z 546.10 (M⁺+H)

Example 4

[0127][4S-(4a,5,5a,6,12a)]-4-(Dimethylamino)-9-[(N,N-dimethylaminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphtacenecarboxamide

[0128] MS (e.s.+): m/z 545.22 (M⁺+H)

[0129][4S-(4a,5,5a,6,12a)]-4-(Dimethylamino)-9-[(N-isopropylaminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphtacenecarboxamide

[0130] MS (e.s.+): m/z 559.24 (M⁺+H)

[0131][4S-(4a,5,5a,6,12a)]-4-(Dimethylamino)-9-[(N-(2-propenyl)aminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphtacenecarboxamide

[0132] MS (e.s.+): m/z 557.19 (M⁺+H)

[0133][4S-(4a,5,5a,6,12a)]-4-(Dimethylamino)-9-[(1-pyrrolidinocarbonyl)methyl]amino1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphtacenecarboxamide

[0134] MS (e.s.+): m/z 571.13 (M⁺+H)

[0135][4S-(4a,5,5a,6,12a)]-4-(Dimethylamino)-9-[(iso-propoxycarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphtacenecarboxamide

[0136] MS (e.s.+): m/z 560.20 (M⁺+H)

[0137][4S-(4a,5,5a,6,12a)]-4-(Dimethylamino)-9-[(N-benzylaminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphtacenecarboxamide

[0138] MS (e.s.+): m/z 607.20 (M⁺+H)

[0139][4S-(4a,5,5a,6,12a)]-4-(Dimethylamino)-9-[(N-ethylaminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphtacenecarboxamide

[0140] MS (e.s.+): m/z 545.2 (M⁺+H)

[0141][4S-(4a,5,5a,6,12a)]-4-(Dimethylamino)-9-[(N-cyclohexylaminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphtacenecarboxamide

[0142] MS (e.s.+): m/z 599.3 (M⁺+H)

[0143][4S-(4a,5,5a,6,12a)]-4-(Dimethylamino)-9-[(1-piperidinocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphtacenecarboxamide

[0144] MS (e.s.+): m/z 585.2 (M⁺+H)

[0145][4S-(4a,5,5a,6,12a)]-4-(Dimethylamino)-9-[(N-(2-methoxyethyl)amino-carbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphtacenecarboxamide

[0146] MS (e.s.+): m/z 575.2 (M⁺+H)

[0147][4S-(4a,5,5a,6,12a)]-4-(Dimethylamino)-9-[(N-cyclobutylaminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphtacenecarboxamide

[0148] MS (e.s.+): m/z 571.3 (M⁺+H)

[0149][4S-(4a,5,5a,6,12a)]-4-(Dimethylamino)-9-[(N-(2-tetrahydrofurylmethyl)-aminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphtacenecarboxamide

[0150] MS (e.s.+): m/z 601.3 (M⁺+H)

[0151][4S-(4a,5,5a,6,12a)]-4-(Dimethylamino)-9-[(N-(3,3-dimethylbutyl)aminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphtacenecarboxamide

[0152] MS (e.s.+): m/z 601.3 (M⁺+H)

[0153][4S-(4a,5,5a,6,12a)]-4-(Dimethylamino)-9-[(N-methylaminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphtacenecarboxamide

[0154] MS (e.s.+): m/z 531.2 (M⁺+H)

[0155][4S-(4a,5,5a,6,12a)]-4-(Dimethylamino)-9-[(N-cyclopropylaminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphtacenecarboxamide

[0156] MS (e.s.+): m/z 557.2 (M⁺+H)

[0157][4S-(4a,5a,12a)]-4,7-Bis(dimethylamino)-9-[(N,N-dimethylaminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphtacenecarboxamide

[0158] MS (e.s.+): m/z 558.19 (M⁺+H)

[0159][4S-(4a,5a,12a)]-4-(Dimethylamino)-9-[(N,N-dimethylaminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphtacenecarboxamide

[0160] MS (e.s.+): m/z 515.09 (M⁺+H)

[0161][4S-(4a,5a,12a)]-4-(Dimethylamino)-9-[(N-isopropylaminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphtacenecarboxamide

[0162] MS (e.s.+): m/z 529.09 (M⁺+H)

[0163][4S-(4a,5a,12a)]-4-(Dimethylamino)-9-[(N-ethylaminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphtacenecarboxamide

[0164] MS (e.s.+): m/z 515.2 (M⁺+H)

[0165][4S-(4a,5a,12a)]-4-(Dimethylamino)-9-[(N-(2-N′,N′-dimethylaminoethyl)aminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphtacenecarboxamide

[0166] MS (e.s.+): m/z 558.3 (M⁺+H)

[0167][4S-(4a,5a,12a)]-4-(Dimethylamino)-9-[(N-cyclopropylaminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphtacenecarboxamide

[0168] MS (e.s.+): m/z 527.2 (M⁺+H)

[0169][4S-(4a,5a,12a)]-4-(Dimethylamino)-9-[(1-pyrrolidinoaminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphtacenecarboxamide

[0170] MS (e.s.+): m/z 541.2 (M⁺+H)

[0171][4S-(4a,5a,12a)]-4-(Dimethylamino)-9-[(N-cyclopentylaminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphtacenecarboxamide

[0172] MS (e.s.+): m/z 555.3 (M⁺+H)

[0173][4S-(4a,5a,12a)]-4-(Dimethylamino)-9-[(N-(2-propenyl)aminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphtacenecarboxamide

[0174] MS (e.s.+): m/z 527.2 (M⁺+H)

[0175][4S-(4a,5a,12a)]-4-(Dimethylamino)-9-[(N-methylaminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphtacenecarboxamide

[0176] MS (e.s.+): m/z 501.2 (M⁺+H)

[0177][4S-(4a,5a,12a)]-4-(Dimethylamino)-9-[(N-benzylaminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphtacenecarboxamide

[0178] MS (e.s.+): m/z 577.2 (M⁺+H)

[0179][4S-(4a,5a,12a)]-4-(Dimethylamino)-9-[(N-cyclobutylaminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphtacenecarboxamide

[0180] MS (e.s.+): m/z 541.2 (M⁺+H)

[0181] [4S-(4aα, 5α, 5aα, 6α,12aα)-4,7-(bis-dimethylamino)-9-[1-(ethoxycarbonyl)ethyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide

[0182] MS (e.s.)+: m/z 573.3 (M⁺+H)

[0183] [4S-(4aα, 5α, 5aα, 6α,12aα)-4-(dimethylamino)-9-[(ethoxycarbonyl)-2-propyl-methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5, 10,12,12a-pentahydroxy-1,11-dioxo-6-methyl-2-naphthacenecarboxamide

[0184] MS (e.s.)+: m/z 588.3 (M⁺+H)

[0185] [4S-(4aα, 5α, 5aα, 6α,12aα)-4-(dimethylamino)-9-[(ethoxycarbonyl)-2-carbonylethoxymethyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-1,11-dioxo-6-methyl-2-naphthacenecarboxamide

[0186] MS (e.s.)+: m/z 618.2 (M⁺+H)

Biological Examples

[0187] Example no. 1 2 3 4 Organism MIC(μg/ml) MIC(μg/ml) MIC(μg/ml)MIC(μg/ml) S. aureus RN4250 16 2 2 — S. aureus RN450 16 0.25 0.5 — S.aureus ATCC29213 16 — — 0.5 S. aureus ATCC 13709 — 0.5 1 — E. hirae ATCC9790 8  0.25 1 — S. pneumoniae ATCC 49619 32 0.5 0.5 0.06 S. pneumoniae157E — 1 — — H. influenzae ATCC 49247 32 32 8 2 M. catarrhalis ATCC23246 4  1 2 — E. coli 1850E 32 64 32 — E. coli ATCC 25933 — — — 2

[0188] Growth-inhibitory activity was determined on liquid medium by theantibiotic dilution technique using 96-well microtiter system platescontaining two-fold dilutions of antibiotic-agent in 0.2 ml. ofMueller-Hinton broth. Plates were inoculated with each test organism toyield a final inoculum of 5×10⁵ CFU/ml and were incubated aerobically at37° C. for 18 h. The MIC was defined as the lowest concentration ofantibacterial agent that inhibited development of visible growth in themicrodilution wells.

Equivalents

[0189] Those skilled in the art will recognize, or be able to ascertainusing no more than routine experimentation, numerous equivalents to thespecific procedures described herein. Such equivalents are considered tobe within the scope of the present invention and are covered by thefollowing claims. The contents of all references, patents, and patentapplications cited throughout this application are hereby incorporatedby reference. The appropriate components, processes, and methods ofthose patents, applications and other documents may be selected for thepresent invention and embodiments thereof.

1. A compound of formula (I):

wherein: R represents hydrogen, halogen, C₁₋₆alkyl or NRaRb; R¹represents hydrogen, C₁₋₆alkyl or together R¹ and R³ represent a CH₂moiety; R² represents hydrogen, —OC₁₋₆alkyl, —O(O)C₁₋₆alkyl or hydroxy;R³ represents hydrogen, hydroxy or together R³ and R¹ represent a CH₂moiety; R⁴ represents hydrogen or C₁₋₆alkyl; R⁵ represents hydrogen,C₁₋₆alkyl or C₁₋₆alkoxycarbonyl; X represents NRxRy or —OC₁₋₆alkyloptionally substituted by one or more groups selected from hydroxy,methoxy, halogen, amino and trifluoromethyl; Ra and Rb independentlyrepresent hydrogen or C₁₋₆alkyl; Rx and Ry independently representhydrogen, benzyl, C₃₋₆cycloalkyl, C₃₋₆alkenyl, C₃₋₆alkynyl, C₁₋₆alkyloptionally substituted by one or more groups selected from hydroxy,methoxy, halogen, NRaRb and trifluoromethyl, —C₁₋₆alkylcycloalkyl,—C₁₋₆alkylheterocycle, C₁₋₆alkylamino and C₁₋₆alkylthio or together Rxand Ry form a heterocycle; and pharmaceutically acceptable derivativesand solvates thereof.
 2. A method for the treatment of a tetracyclinecompound responsive state in a subject, which comprises administering tothe subject an effective amount of a compound of claim
 1. 3. The methodof claim 2, wherein said subject is a human.
 4. A compound of claim 1for use in medical therapy.
 5. Use of a compound of claim 1 for themanufacture of a medicament for the treatment of a tetracycline compoundresponsive state.
 6. A pharmaceutical formulation comprising a compoundof claim 1 and one or more pharmaceutically acceptable carriers.